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Haifeng Tang,
Yan Yan,
Zhe Feng,
Reynalda K de Jesus,
Lihu Yang,
Dorothy A Levorse,
Karen A Owens,
Taro E Akiyama,
Raynald Bergeron,
Gino A Castriota,
Thomas W Doebber,
Kenneth P Ellsworth,
Michael E Lassman,
Cai Li,
Margaret S Wu,
Bei B Zhang,
Kevin T Chapman,
Sander G Mills,
Joel P Berger, Alexander Pasternak
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ABSTRACT: A new series of thiazole-substituted 1,1,1,3,3,3-hexafluoro-2-propanols were prepared and evaluated as malonyl-CoA decarboxylase (MCD) inhibitors. Key analogs caused dose-dependent decreases in food intake and body weight in obese mice. Acute treatment with these compounds also led to a drop in elevated blood glucose in a murine model of type II diabetes.
Bioorganic & medicinal chemistry letters 10/2010; 20(20):6088-92. · 2.65 Impact Factor
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ABSTRACT: Inhibition of CCR2 has been considered as a target for multiple therapeutic diseases including autoimmune disease, atherosclerosis, pain, and metabolic disease, based in part on the critical role this receptor plays on monocyte migration. Numerous companies have reported programs to identify CCR2 antagonists. Common challenges to the development of CCR2 agents have included poor activity at the rodent receptor and selectivity for both other chemokine receptors and ion channels. This review summarizes the rationale for targeting CCR2 in disease, the recent progress in the identification of potent and select CCR2 antagonists, and the current status of clinical trials for CCR2 agents.
Current topics in medicinal chemistry 01/2010; 10(13):1278-98. · 4.47 Impact Factor
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Alexander Pasternak,
Stephen D. Goble,
Mary Struthers,
Pasquale P. Vicario,
Julia M. Ayala,
Jerry Di Salvo,
Ruth Kilburn,
Thomas Wisniewski,
Julie A. DeMartino,
Sander G. Mills,
Lihu Yang
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ABSTRACT: This report describes the discovery of a potent, orally bioavailable CC chemokine receptor 2 (CCR2) antagonist which, while optimized for CCR2 potency, also had potent CC chemokine receptor 5 (CCR5) activity.Keywords: CCR2; CCR5; chemokine, dual antagonist
12/2009;
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Alexander Pasternak,
Stephen D Goble,
Reynalda K deJesus,
Donna L Hreniuk,
Christine C Chung,
Michael R Tota,
Paul Mazur,
Scott D Feighner,
Andrew D Howard,
Sander G Mills,
Lihu Yang
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ABSTRACT: This Letter describes optimization of ghrelin receptor antagonists and inverse agonists starting from a screening hit.
Bioorganic & medicinal chemistry letters 08/2009; 19(21):6237-40. · 2.65 Impact Factor
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Shankaran Kothandaraman,
Karla L Donnely,
Gabor Butora,
Richard Jiao, Alexander Pasternak,
Gregori J Morriello,
Stephen D Goble,
Changyou Zhou,
Sander G Mills,
Malcolm Maccoss,
Pasquale P Vicario,
Julia M Ayala,
Julie A Demartino,
Mary Struthers,
Margaret A Cascieri,
Lihu Yang
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ABSTRACT: A series of novel 1-aminocyclopentyl-3-carboxyamides incorporating substituted tetrahydropyran moieties have been synthesized and subsequently evaluated for their antagonistic activity against the human CCR2 receptor. Among them analog 59 was found to posses potent antagonistic activity.
Bioorganic & medicinal chemistry letters 01/2009; 19(6):1830-4. · 2.65 Impact Factor
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Alexander Pasternak,
Stephen D Goble,
George A Doss,
Nancy N Tsou,
Gabor Butora,
Pasquale P Vicario,
Julia Marie Ayala,
Mary Struthers,
Julie A Demartino,
Sander G Mills,
Lihu Yang
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ABSTRACT: In an effort to shed light on the active binding conformation of our 3-amino-1-alkyl-cyclopentane carboxamide CCR2 antagonists, we prepared several conformationally constrained analogs resulting from backbone cyclization. Evaluation of CCR2 binding affinities for these analogs gave insight into the optimal relative positions of the piperidine and benzylamide moieties while simultaneously leading to the discovery of a new, potent lead type based upon a spirocyclic acetal scaffold.
Bioorganic & medicinal chemistry letters 03/2008; 18(4):1374-7. · 2.65 Impact Factor
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ABSTRACT: This report describes replacement of the 4-(4-fluorophenyl)piperidine moiety in our CCR2 antagonists with 4-heteroaryl piperidine and 4-(carboxyphenyl)-piperidine subunits. Some of the resulting analogs retained potency in our CCR2 binding assay and had improved selectivity versus the I(Kr) channel; poor selectivity against I(Kr) had been a liability of earlier analogs in this series.
Bioorganic & medicinal chemistry letters 03/2008; 18(3):994-8. · 2.65 Impact Factor
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ABSTRACT: A systematic examination of the central aromatic portion of the lead (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(1'H-spiro[indene-1,4'-piperidin]-1'-yl)butanamide (9) led to the discovery of a novel class of CCR2 receptor antagonists, which carry small alicyclic groups such as cyclopropyl, cylobutyl, or cyclopropylmethyl attached at C2 of the carbon backbone. The most potent compound discovered, namely (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-[(1R,3'R)-3'-methyl-1'H-spiro[indene-1,4'-piperidin]-1'-yl]butanamide (29), showed very high binding affinity (IC50 = 4 nM, human monocyte) and excellent selectivity toward other related chemokine receptors. The excellent pharmacokinetic profile of this new lead compound allows for extensive in vivo evaluation.
Bioorganic & Medicinal Chemistry Letters 10/2006; 16(18):4715-22. · 2.55 Impact Factor
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ABSTRACT: Through modification of a screening hit we have discovered a structurally distinct new lead, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-(4-fluorophenyl)-4-(4-phenylpiperidin-1-yl)butanamide (11), which has subsequently served as the departure point for an ongoing program targeting CCR2 antagonists. Optimization of 11 leading to antagonists 26 and 37 is described. Antagonist 26 was shown to have good oral bioavailability in rats. Antagonist 37 had a CCR2 IC50 of 59 nM and excellent potency in a functional assay measuring inhibition of MCP-1 induced monocyte chemotaxis (IC50 of 41 nM).
Journal of Medicinal Chemistry 09/2006; 49(16):4801-4. · 5.25 Impact Factor
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Lihu Yang,
Changyou Zhou,
Liangqin Guo,
Gregori Morriello,
Gabor Butora, Alexander Pasternak,
William H Parsons,
Sander G Mills,
Malcolm MacCoss,
Pasquale P Vicario,
Hans Zweerink,
Julia M Ayala,
Shefali Goyal,
William A Hanlon,
Margaret A Cascieri,
Marty S Springer
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ABSTRACT: Systematic modification of a screening lead yielded a class of potent glycinamide based CCR2 antagonists. The best compound (55, (2S)-N-[3,5-bis(trifluoromethyl)benzyl]-2-{[2-(1-piperidinyl)ethyl]amino}-2-(3-thienyl)acetamide) displayed good binding affinity (IC50=30 and 39 nM) toward human monocytes and CHO cell expressing human CCR2b, respectively. Functionally, it blocked MCP-1 (CCL2)-induced calcium mobilization (IC50=50 nM) and chemotaxis mediated through the CCR2 receptor (9.6 nM). It is selective against other chemokine receptors tested.
Bioorganic & Medicinal Chemistry Letters 08/2006; 16(14):3735-9. · 2.55 Impact Factor
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12/2001: pages 250-252;
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Lihu Yang,
Scott C. Berk,
Susan P. Rohrer,
Ralph T. Mosley,
Liangqin Guo,
Dennis J. Underwood,
Byron H. Arison,
Elizabeth T. Birzin,
Edward C. Hayes,
Sudha W. Mitra, [......],
Bridgette S. Butler,
Forrest Foor, Alexander Pasternak,
Yanping Pan,
Maria Silva,
Roger M. Freidinger,
Roy G. Smith,
Kevin Chapman,
James M. Schaeffer,
Arthur A. Patchett
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ABSTRACT: A series of nonpeptide somatostatin agonists which bind selectively and with high affinity to somatostatin receptor subtype
2 (sst2) have been synthesized. One of these compounds, L-054,522, binds to human sst2 with an apparent dissociation constant
of 0.01 nM and at least 3,000-fold selectivity when evaluated against the other somatostatin receptors. L-054,522 is a full
agonist based on its inhibition of forskolin-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells stably
expressing sst2. L-054,522 has a potent inhibitory effect on growth hormone release from rat primary pituitary cells and glucagon
release from isolated mouse pancreatic islets. Intravenous infusion of L-054,522 to rats at 50 μg/kg per hr causes a rapid
and sustained reduction in growth hormone to basal levels. The high potency and selectivity of L-054,522 for sst2 will make
it a useful tool to further characterize the physiological functions of this receptor subtype.
Proceedings of the National Academy of Sciences 08/1998; 95(18):10836-10841. · 9.68 Impact Factor
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06/1998;
